Hematopoiesis is the normal formation of blood cells in the bone marrow. Blood cells develop from pluripotential hematopoietic stem cells. The first step in the hematopoietic differentiation process is the commitment of the stem cell to one of two large pathways: myeloid or lymphoid. A myeloid stem cell then matures into a myeloid blast. This blast can form red blood cells, platelets or several types of white blood cells. A lymphoid stem cell matures into a lymphoid blast, which forms into one of several types of white blood cells, such as B cells or T cells. Most blood cells mature in the bone marrow and then move into the blood vessels. Hematopoiesis takes place in a region termed the bone marrow niche. In addition to hematopoietic stem cells, endothelial cells, stromal cells, adipocytes, fibroblasts, and bone cells are found in this niche.
It has long been appreciated that trabecular bone formation and establishment of hematopoiesis within the bone marrow cavity are intimately coordinated (Dennis and Charbord (2002)). Osteoblasts, the bone forming cells, in particular, are in close contact with hematopoietic stem cells, and have been highlighted as a defining component of the hematopoietic stem cell niche controlling the homing and development of neighboring hematopoietic stem cells (HSCs) (Raaijmakers et al. (2010); Castillo and Jacobs (2010); Levesque, Helwani, and Winkler (2010); Dennis and Charbord (2002)). Primitive hematopoietic cells in the bone marrow and implanted lineage-negative HSCs localize adjacent to the endosteal surface where osteoblasts reside, whereas rarely cycling HSCs sporadically attach to endosteal osteoblasts (Oh and Kwon (2010); Gong (1978)). In addition, a functional interaction between the two cell types involving engagement of the Notch1/Jag1 signaling pathway between HSCs and osteoblasts, promotes HSC proliferation (Calvi et al. (2003); Zhang et al. (2003)). Transgenic and knockout mouse models have indicated parallel, concordant alterations in osteoblast precursor numbers or mesenchymal cells of the osteolineage, and the number of long term repopulating HSCs (LT-HSCs), as well as subsequent defects in bone marrow hematopoiesis and the development of extramedullar hematopoiesis (Mendez-Ferrer et al. (2010); Wu et al. (2008); Visnjic et al. (2004); Calvi et al. (2003); Zhang et al. (2003)). Genetic evidence has now lent support to the idea that osteoblast progenitors or mesenchymal stem cells (MSCs) with osteoblastic capability are implicated in HSC mobilization and lineage determination survival and proliferation (Mendez-Ferrer et al. (2010); Wu et al. (2008); Mayack and Wagers (2008); Zhu et al. (2007); Taichman et al. (1996); Taichman and Emerson (1994)).
In a more precise manner of regulation, the information received by HSCs seems to be influenced by the differentiation stage of the osteoblast. Nestin-expressing cells of the mesenchymal osteolineage affect homing of HSC progenitors to the bone marrow (Mendez-Ferrer et al. (2010)). Osterix-expressing early osteoblast progenitors initiate ectopic HSC niche formation and regulate B lymphopoiesis (Chan et al. (2009); Wu et al. (2008)). In contrast, osteoclasts, the bone resorbing cells, appear to be dispensable for the maintenance and mobilization of HSCs (Miyamoto et al. (2011)).
The mechanisms by which osteoblasts influence hematopoiesis are just now being deciphered. Osteoblast-induced increases in HSCs and selective expansion of the erythroid lineage can be cause by elevated HIF/EPO signaling in osteoblasts. Osteoblasts also support B lymphocyte commitment and differentiation from hematopoietic stem cells (Zhu et al. 2007). However, little is known about the role of osteoblasts in hematologic diseases.
Irregular hematopoiesis can lead to numerous conditions including cancers of the blood, such as leukemia, lymphoma, and myeloma, and myelodysplastic syndromes. In these patients, the abnormal hematopoiesis leads to the generation of high numbers of abnormal, or cancerous, cells. The accumulation of these irregular cells in the marrow, blood and/or lymphatic tissue interferes with the production and functioning of normal red cells, white cells and platelets (The Leukemia and Lymphoma Society, Facts 2010-2011, page 3). Additionally, irregular hematopoiesis can cause other disorders of the blood.
Every ten minutes, someone in the United States dies from a blood cancer. There will be an estimated 54,020 deaths from leukemia, lymphoma, and myeloma this year. In 2010, it was estimated that 43,050 people would be diagnosed with leukemia, and 21,840 people would die of the disease. Moreover, leukemia causes about one-third of all cancer deaths in children younger than 15 years (The Leukemia and Lymphoma Society, Facts 2010-2011, page 1).
While there are several known treatments for blood cancers, including chemotherapy, radiation, immunotherapy, gene therapy, and stem cell transplantation, there is still a poor prognosis. In patients who are 65 years or older (65 is the median age at diagnosis), survival rates following chemotherapy are in the range of 10%. In younger patients, the survival rate is in the range of 30%, except in the very small fraction of patients. Various modifications of drug delivery and dose have had no significant impact. Additionally, all of these therapies have many unwanted side effects. Chemotherapy can cause extreme fatigue, hair loss, nausea, loss of appetite, and greater risks of infection. Radiation can cause extreme fatigue. Immunotherapy can cause headache, muscle aches, fever, weakness, and anemia. There is a risk of graft-versus-host disease with stem cell transplantation (The Leukemia and Lymphoma Society, Facts 2010-2011, page 3-6). While molecular studies have further refined an understanding of the defects in this disease, none have provided a target for therapy.
Bone cancer is a malignant tumor of the bone that destroys normal bone tissue. Malignant tumors that begin in the bone are called primary bone cancer. Cancer that metastasizes to the bones from other parts of the body is called metastatic cancer and named from the organ from which it spread. Bone cancer is treated with surgery, chemotherapy, radiation, and cryosurgery. All of these treatments have the same unwanted side effects.
Thus, there is a need for the development of additional therapies for leukemia, as well as other blood and bone cancers, those without the unwanted, potentially dangerous side effects.
The emerging role of osteoblasts in hematologic malignancies makes these cells a novel potential target for the treatment of in leukemia and other malignancies and blood disorders.
Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter that modulates both central and peripheral function with both synaptic and paracrine activities, acting on neurons, smooth muscle, and other cell types. Close to ninety percent (90%) of serotonin is synthesized and stored in the gastrointestinal (GI) system, where it mediates sensations between the GI tract and the brain (Berger, Gray, and Roth (2009); Gershon and Tuck (2007)). The remainder of serotonin is found in the central nervous system (CNS) where it helps to regulate mood, appetite, sleep and other behavioral functions, as well as cognitive functions.
Serotonin is synthesized from tryptophan by the enzyme tryptophan hydrolase (Tph) and aromatic amino acid decarboxylase. Two isoforms of Tph have been discovered: Tph1, primarily expressed in the pineal gland and nonneuronal tissue, such as enterochromaffin (EC) cells in the duodenum, and Tph2, exclusively expressed in the neuronal cells (Patel et al. (2004); Côtè et al. (2003)). Given that serotonin cannot cross the blood-brain barrier, these two genes are solely responsible for regulating the level of this molecule in the periphery and in the brain, respectively.
Peripheral or gut-derived serotonin (GDS) is secreted from EC cells in reaction to stimuli, such as distenstion or chemicals, and the secreted serotonin increases the motility of the gut. Several disorders are linked to the dysregulation of peripheral serotonin including GI disorders, emesis, and heart valve damage (Gershon (2005); Gershon (2003); Kulke and Mayer (1999); Andrews et al. (1990)).
Recently, gut-derived serotonin has also been shown to inhibit osteoblast proliferation and bone formation that does not affect bone resorption (Yadav et al. (2008)).